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Thymidine derivatives and their preparation and use
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A technology for use and preparation of drugs, which is applied in the field of medicine and can solve the problems of low susceptibility of FU-based antitumor agents
Active Publication Date: 2020-10-30
NANKAI UNIV
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The main effect of FU-based antitumor agents widely used in clinical practice is considered to be TS inhibition, but it has been reported that there are patients with low sensitivity to FU-based antitumor agents
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Embodiment 1
[0125] Example 1: Compound F 2 Preparation of TDR
[0126]
[0127] Weigh 456.4mg of deoxyuridine, 1.1g of sodium difluoromethanesulfinate, 101mg of rose bengal (CAS No.632-69-9) into a 50ml reaction tube, add 20ml of dimethyl sulfoxide, green at room temperature The reaction was stirred under visible light for 48 hours. After the reaction, 20 ml of water was added, extracted with ethyl acetate, washed with saturated brine, dried over anhydroussodiumsulfate, filtered, spin-dried, and separated by column to obtain 295 mg of solid.
[0128] 1 H NMR (400MHz, CD 3 CN)δ9.30(s,1H),8.15(s,1H),6.38(t,J=54.8Hz,1H),5.93(t,J=6.3Hz,1H),4.16-4.11(m,1H) ,3.67(q,J=3.3Hz,1H),3.57-3.45(m,2H),3.19(t,J=4.8Hz,1H),2.02-1.94(m,2H),1.74-1.72(m,1H ); HRMS(ESI) calcd for C 10 h 12 f 2 N 2 o 5 [M-H + ]:277.0636,found:277.0640.
Embodiment 2
[0129] Example 2 Compound F 2 Evaluation of Inhibitory Activity of TDR and Trifluorothymidine on HCT116 Cells
[0130] 2.1 Experimental samples
[0131] Compound F2TDR was prepared by the method in Example 1. Trifluorothymidine was purchased from Shanghai Haohong Biomedical Technology Co., Ltd., and mouse-derived colorectal cancercell HCT116 was provided by Peking Union Medical College CellBank.
[0132] 2.2 Experimental method
[0133] HCT116 cells used McCoy's 5A medium (containing 10% FBS, 1% penicillin / streptomycin), in 5% CO 2, cultured at a constant temperature of 37°C, compound F 2 TDR and trifluorothymidine were dissolved in PBS (containing 10% DMSO) to prepare solutions.
[0134] Collect the HCT116 cells in the logarithmic phase, adjust the concentration of the cell suspension, inoculate the cell suspension in a 96-well plate, and spread the plate to make the cell density to be tested to about 5000 / well, 100 μL of the cell suspension per well, in 5% CO 2 , incu...
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Abstract
The invention belongs to the field of medicine, and particularly relates to a thymidine derivative, a preparation method and application thereof. The thymidine derivative, the preparation method and application thereof mainly relate to a compound, and a racemate, stereoisomer, tautomer, nitrogenoxide, solvate or pharmaceutically acceptable salt thereof represented by formula I, and the preparation method and application thereof. According to the thymidine derivative, the preparation method and application thereof, compounds have better inhibitory activity on cancer cells, especially colorectal cancer cells than FTD, the drug activity is significantly improved, and promising application prospects are obtained. Moreover, the compounds are safe for normal cells in the human body. The invention further provides a method for preparing the compound represented by the formula I in one step by using a green solvent under mild conditions starting from simple and cheap raw materials.
Description
technical field [0001] The invention belongs to the field of medicine, and in particular relates to thymidine derivatives and their preparation methods and uses. Background technique [0002] Many cancers are very difficult to detect in the early stage, and some serious symptoms will appear only in the advanced stage, and the cancer in the advanced stage is very difficult to treat. Colorectal cancer is one of the most common non-skin cancers among men and women in the United States, according to research data from the National Cancer Institute. This cancer is very difficult to treat and is the second leading cause of cancer death in the United States, after lung cancer, the number one cancer worldwide. [0003] The nucleosidemetabolism inhibitor trifluorothymidine (trifluridine, FTD) is a nucleic acid derivative in which the 5th methyl group of thymidine is replaced with a trifluoromethyl group, which can be directly embedded in DNA and interfere with DNA synthesis, thereb...
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